Clonal Dynamics of the antibody response

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PROJECT SUMMARY Generating an appropriate antibody response is critical for protection against reinfection and for the effectiveness of vaccination, particularly in the context of viral diseases. In addition to well-studied quantitative parameters such as antibody titer and affinity, other, more qualitative parameters related to the clonal composition of the response also play critical roles in antibody-mediated protection. These include antigen and epitope specificity, which is key to viral neutralization capacity and antibody breadth, and overall clonal diversity, which strongly influences the degree of immunodominance and therefore the ability of viruses to escape immunity by mutation. Despite their importance, such “ecological” aspects of GC biology remain poorly understood and systematically understudied at the mechanistic level. Our long-term goal is to develop a mechanistic understanding of how the competitive waxing and waning of B cell clones at the various stages of the immune response shapes the ultimate composition, specificity, and protective efficacy of serum antibody. In our previous studies, using multicolor “Brainbow”-based B cell fate- mapping models, we focused on the germinal center (GC) and memory phases of the response, revealing how highly diverse early responders are funneled towards oligoclonality, first progressively by GC selection (including in chronic gut-associated GC) and then dramatically by secondary boosting. We now propose to extend our work using these same tools to investigate the clonal dynamics of prolonged selection in long-lived virus-induced GCs (Aim 1) and of the progressive differentiation of plasmablasts and plasma cells from GC precursors (Aim 2). We also propose a new “molecular fate-mapping” system to determine how clonal dynamics impact the ultimate composition of serum antibody (Aim 3). This allows us to investigate the B cell biology of serum-level phenomena such as antigenic imprinting/original antigenic sin, immunodominance, and viral escape. We expect our findings will provide greater mechanistic understanding of how the composition and protective effectiveness of serum antibody is determined by the dynamics of B cell clonal competition, with implications for the design of effective vaccination strategies for influenza, HIV, and SARS-CoV-2.